Aqueous antacids with calcium carbonate and magnesium salt

ABSTRACT

The present invention relates to an aqueous pharmaceutical suspension for oral use, and a method of preparation, having antacid and antiulcer properties which contains a therapeutically effective amount of calcium carbonate in combination with magnesium carbonate and/or magnesium trisilicate and a carboxylic acid pH adjusting agent.

This is a division of application Ser. No. 08/153,005, filed Nov. 12,1993, now U.S. Pat. No. 5,455,050 which is hereby incorporated byreference.

FIELD OF THE INVENTION

This invention relates to new pharmaceutically elegant antacidcompositions and their method of preparation. More specifically, thisinvention relates to aqueous pharmaceutical suspensions for oral usehaving antacid and antiulcer properties which contain a therapeuticallyeffective amount of calcium carbonate in combination with magnesiumcarbonate and/or magnesium trisilicate as the sole active antacidcomponent.

BACKGROUND OF THE INVENTION

Calcium carbonate, magnesium carbonate and magnesium trisilicate areknown gastric antacids (for example, see Remington's PharmaceuticalSciences, 18th Edtn., 1990, published by Mack Publishing Co., Chapter 39on "Gastrointestinal Drugs) with relatively fast onset of action andprolonged duration of action. However, as noted on page 779 of theRemington reference, which provides a tabular listing of twenty-sixproprietary antacid suspensions, only one indicates a combination ofcalcium carbonate with a magnesium salt (magnesium carbonate) for theproduct Marblen (Fleming).

It has been observed that aqueous antacid suspensions of calciumcarbonate in combination with magnesium carbonate and/or magnesiumtrisilicate yield very alkaline compositions with a pH of about 9 oreven higher to about 9.9. Such high alkalinity is disadvantageous forcomercial purposes, for example, preservatives in the formulation suchas parabens will break down and lose efficacy over time at such highpH's.

SUMMARY OF THE INVENTION

The present invention thus provides aqueous antacid suspensions with alower pH of about 7.5-8.5, and preferably about 8.0-8.3, with as theantacid component the commercially seldom used calcium carbonate,magnesium carbonate and/or magnesium trisilicate antacids. In additionto a commercially acceptable pH range, the suspensions of this inventionare stable with regard to viscosity, defoaming, sedimentation and acidneutralizing capacity (ANC) parameters and redisperse well upon shaking.As described hereinafter, it is the selective order of mixing theessential components of the present invention which provides thedesirably lower pH.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The aqueous suspensions of the present invention contain an effectiveantacid amount of calcium carbonate in combination with a magnesium saltselected from the group consisting of magnesium carbonate, magnesiumtrisilicate and mixtures thereof. This calcium carbonate/magnesium saltcombinate is the sole active antacid component in the suspension. Thesuspension contains from about 1.5 to about 20, preferably about 5 toabout 15, percent weight/volume of the calcium carbonate and from about1.0 to about 20, preferably about 2 to about 8, percent weight/volume ofthe magnesium salt, based on the volume of the aqueous antacidsuspension.

The calcium carbonate, magnesium carbonate and magnesium trisilicateactive ingredients are utilized in the present invention as individualpowders rather than in gel or paste form. Micronized powders are foundto be most suitable, preferably with 100% particle size distribution ofabout 0.1-20, and preferably about 0.1-10 microns. Such small particlesize has a tremendous advantageous effect on the sedimentation rate ofthe suspension and, more importantly, it helps achieve optimal mouthfeelto the user.

The present invention also makes use of an effective suspending amountof a suitable thickening agent generally used in aqueous antacidformulations, for example, xanthan gum (preferred), guar gum, methylcelluloses such as hydroxypropyl methyl cellulose (HPMC) and sodiumcarboxy-methylcellulose, and the like. Since the active antacids areutilized in powder form instead of gels or pastes, which tend tocontribute more to the final viscosity, the thickening agent componentneeds to provide a substantial viscosity to the finished product. Forpurposes of this invention, the particular thickening agent(s) employed,and the amount thereof, should be such so as to provide a viscosityrange in the final product of from about 1000 centipoise (cps) to about3000 cps, as determined on a Brookfield LVT viscometer (25° C., spindleno. 2, rotation speed 12 for 3 minutes). In general, from about 0.1 toabout 1.0 percent weight/volume of the thickening agent, based on thevolume of final product, has been found suitable.

An appropriate liquid wetting agent such as glycerin may be utilized toinsure maximum dispersion of the thickening agent in the aqueous system.From about 0.5 to about 20.0, and preferably from about 2.0 to about 7.5weight/volume percent of glycerin has been found suitable. Thethickening agent is dispersed in the glycerin in a separate containerwith thorough mixing prior to its utilization. An alternative to thethickening agent/glycerin premix is the use of appropriate mechanicaldispersing means such as a high shear mixer to assist dispersion of thethickening agent. A further alternative is to use one of the readilydispersible thickening agents commercially available, for example, theKELTROL RD brand of readily dispersed xanthan gum from Kelco, divisionof Merck. Such readily dispersible thickening agents provide adequatedispersion upon direct addition to the aqueous system. The need forpremixing with a wetting agent is thus eliminated although premixing maystill be utilized.

As noted previously, the high pH levels inherent in the use of magnesiumcarbonate and/or magnesium trisilicate, about 9 or higher, are deemedtoo high to achieve and maintain an efficient preservative system.Accordingly, a carboxylic acid pH adjusting agent is included as anessential component of the present invention. Tartaric acid has beenfound to be the preferred pH adjusting agent, although other carboxylicacids such as adipic, benzoic, carbonic, cinnamic, citric, fumaric,glutaric, gluconic, hydroxybenzoic, malonic, malic, phthalic, oxalic,sorbic, succinic and the like may be utilized. The amount of thecarboxylic acid pH adjusting agent should be sufficient to bring andmaintain the pH of the final product in a range of about 7.5-8.5 andpreferably about 8.0-8.3. In general from about 0.2 to about 2.0weight/volume percent of the pH adjusting agent has been found suitable.For example, with about 0.5 weight/volume percent of tartaric acid, astable pH of about 8.2 has been maintained at one year.

Any desired pharmaceutically acceptable adjuvant used in liquid antacidpreparations by those skilled in the art may also be employed. Forexample, one or more preservatives such as methylparaben, butylparabenor propylparaben, and sweetening and/or flavoring agents such as oil oforange, imitation wintergreen flavor, lemon-lime flavors, mint flavors,or combinations thereof, are commonly utilized. Sorbitol serves toincrease shelf life and palatability. Further, other actives such asantispasmodic agents, tranquilizers or other medicaments can beoptionally included. Simethicone, for example, which is not an antacid,is an antiflatuent frequently used in antacid compositions to defoamgastric juice in order to decrease the incidence of gastroesophagealreflux. In general, an effective antiflatuent amount is employed, andfrom about 0.1 to about 2.0 weight/volume percent is found suitable.

A unique aspect of the present invention is the order in which theessential components are mixed in order to achieve this desired pH rangeof about 7.5-8.5, and preferably about 8.0-8.3. If the pH adjustingagent is added to the active antacids prior to the thickening agent, ittends to react with the active antacids and the result is a higher pH(>9). It is critical, therefore, that the thickening agent be added tothe aqueous dispersion of the particulate antacids with thoroughadmixture prior to addition of the pH adjusting agent. The thickeningagent is stirred for a time sufficient to substantially coat theparticulate antacids such that the grittiness perceived from thepowdered materials is negligible and, more importantly, the protectivecoating prevents unwanted reaction between the carboxylic acid pHadjusting agent and the active antacids and the result is a lower pH.

In the event that other additives or active medicaments are to beincluded which are likewise susceptible to reaction or degradation withthe carboxylic acid pH adjusting agent, for example, simethicone, thenthese should be either similarly precoated with the thickening agent orutilized in the form of a compatible liquid. Preferably the simethiconeis in the form of an aqueous dispersion or emulsion. These dispersionsand emulsions are commercially available, and generally contain about30-50 weight/volume percent of simethicone, based on the volume of theaqueous dispersion or emulsion.

The present invention thus provides a method of preparing a stableaqueous antacid suspension for oral use with a pH about 7.5-8.5 ofcalcium carbonate in combination with a magnesium salt consisting ofmagnesium carbonate, magnesium trisilicate or a mixture thereof, whichcomprises in the order specified the steps of:

(a) adding to water an effective antacid amount of particulate calciumcarbonate and said magnesium salt, each in the form of a micronizedpowder with 100% particle size distribution of about 0.1-20, preferablyabout 0.1-10, microns with mixing until the particulate material iscompletely wetted and dispersed;

(b) adding to said dispersion with stirring from about 0.1 to about 1.0weight/volume percent of a thickening agent for a time sufficient tosubstantially coat said particulate material and to produce asuspension;

(c) adding to said suspension with stirring an effective amount of acarboxylic acid pH adjusting agent to provide a pH of about 7.5-8.5 tothe final aqueous antacid suspension; and

(d) optionally adding with stirring at least one pharmaceuticallyacceptable adjuvant or at any of steps (a), (b) or (c).

If deemed necessary, the following additional steps may be performed:

(e) adding to said suspension water to bring the volume to 100; and

(f) stirring to obtain uniform suspension.

When sorbitol or flavorants or sweeteners or preservatives are added,they may be added to any one of steps (a) to (d).

Prior to packaging, the suspension is sterilized by pasteurization or bychemicals such as sodium hypochlorite or hydrogen peroxide.

The invention will be made clearer in the examples which follow. Allpercentages are weight/volume (grams/liter). These examples are given byway of illustration and are not to be taken as limiting.

EXAMPLE I

The following compositions illustrate the present invention.

    ______________________________________                                                        Percent W/V                                                   Ingredients       A         B                                                 ______________________________________                                        Deionized Water   53.6-66.04                                                                               53.6-66.04                                       Sorbitol          5.0-30.0  10.0-20.0                                         Glycerin          0.5-20.0  2.0-7.5                                           Xanthan Gum (KELTROL RD)                                                                        0.1-1.0   0.25-0.75                                         Simethicone.sup.a 0.5-10.0  1.0-3.0                                           Calcium Carbonate.sup.b                                                                         1.5-20.0   5.0-15.0                                         Magnesium Carbonate.sup.c,d                                                                     1.0-20.0  2.0-8.0                                           Tartaric Acid     0.2-2.0   0.35-0.65                                         Butylparaben      0.02      0.02                                              Propylparaben     0.03      0.03                                              Flavorants (liquid)                                                                             0.3-1.0   0.3-1.0                                           Water Q.S.        100       100                                               pH                7.6-8.5   8.0-8.4                                           ______________________________________                                         .sup.a 30% aqueous emulsion or dispersion                                     .sup.b Average particle size 100% distribution <10 microns.                   .sup.c Average particle size 100% distribution <10 microns.                   .sup.d Alternatively magnesium trisilicate.                              

In a suitable preparation vessel, add the sorbitol to the water and mixfor ten minutes. Add the simethicone and mix for ten minutes. Add thecalcium carbonate and mix for fifteen minutes. Add the magnesiumcarbonate and mix for fifteen minutes. In a separate vessel, add thexanthan gum to the glycerin and mix for fifteen minutes and then addmixture to the preparation vessel with mixing for twenty minutes. Addthe tartaric acid and mix for twenty minutes. In a separate vessel addthe parabens and flavorants and mix until parabens are dissolved andthen add mixture to the preparation vessel with mixing for thirtyminutes. If necessary, add water to bring volume to 100 and continuestirring to obtain uniform suspension. The suspension is thenpasteurized at 70° C. for 2-60 minutes.

EXAMPLE II

The following suspension were prepared using the 10 procedure describedin Example I. The suspension was sterilized by pasteurization at 70° C.for 2 minutes.

    ______________________________________                                                           Percent W/V                                                Ingredients          A        B                                               ______________________________________                                        Deionized Water      66.04    53.6                                            Sorbitol             15.0     15.0                                            Glycerin             5.0      5.0                                             Xanthan Gum (KELTROL RD)                                                                           0.60     0.6                                             Simethicone.sup.a    1.4      2.8                                             Calcium Carbonate.sup.b                                                                            8.0      16.0                                            Magnesium Carbonate.sup.c                                                                          3.0      6.0                                             Tartaric Acid        0.5      0.5                                             Butylparaben         0.02     0.02                                            Propylparaben        0.03     0.03                                            Flavorants (liquid)  0.03-1.0 0.3-1.0                                         Water Q.S.           100      100                                             pH                   8.2      8.2                                             ______________________________________                                         .sup.a 30% aqueous emulsion or dispersion                                     .sup.b Average particle size 100% distribution <10 microns.                   .sup.c Average particle size 100% distribution <10 microns.              

EXAMPLE III

The following suspension was prepared using the procedure of Example I,except the sequence of ingredient addition was modified as shown below.The suspension was not sterilized because of the unacceptable pH.

    ______________________________________                                        Ingredients         Percent W/V                                               ______________________________________                                        Soribtol            15.0                                                      Xanthan Gum (KELTROL T)                                                                           0.3                                                       Simethicone.sup.a   2.7                                                       Calcium Carbonate.sup.b                                                                           16.2                                                      Magnesium Carbonate.sup.c                                                                         5.8                                                       Tartaric Acid       0.5                                                       Butylparaben        0.02                                                      Propylparaben       0.03                                                      Flavors/Saccharin   0.66                                                      Deionized Water Q.S.                                                                              100                                                       pH                  8.85                                                      ______________________________________                                         .sup.a 30% aqueous emulsion or dispersion                                     .sup.b Average particle size 100% distribution <10 microns.                   .sup.c Average particle size 100% distribution <10 microns.              

Sequence of ingredient addition to vessel:

(a) Add sorbitol and water;

(b) Add simethicone;

(c) Add tartaric acid;

(d) Add xanthan gum;

(e) Add calcium carbonate and magnesium carbonate;

(f) Dissolve parabens/saccharin in flavors and add to vessel; and

(g) Q.S. to 1000 ml of water.

When the antacids were added in step (e), the calcium carbonate reacted(foamed) with the tartaric acid because the antacid powders were notadequately coated with the xanthan gum. This example illustrates theimportance of mixing the xanthan gum and the antacid so that the antacidparticles are adequately coated with the gum before the tartic acid isadded to the vessel.

Various modifications can be made to the above-described embodimentswithout departing from the spirit and scope of the present invention.

What is claimed is:
 1. A stable aqueous antacid suspension for oral usehaving a pH of about 7.5 to about 8.5 of calcium carbonate incombination with a magnesium salt selected from the group consisting ofmagnesium carbonate, magnesium trisilicate and a mixture thereof as thesole active antacid component, prepared by a process which comprises inthe order specified the steps of:(a) adding to water an effectiveantacid amount of particulate calcium carbonate and said magnesium salt,each in the particulate form of a micronized powder with 100% particlesize distribution of about 0.1 to about 20 microns with mixing until theparticulate material is completely wetted and dispersed; (b) adding tosaid dispersion with stirring an effective suspending amount of athickening agent for a time sufficient to substantially coat saidparticulate material and to produce a suspension; and (c) adding to saidsuspension with stirring an effective pH adjusting amount of acarboxylic acid pH adjusting agent to provide a pH of about 7.5 to about8.5 to the aqueous antacid suspension.
 2. The suspension of claim 1wherein said antacid amount of calcium carbonate is from about 1.5 toabout 20.0 percent weight/volume and of the magnesium salt is from about1.0 to about 20.0 percent weight/volume, based on the volume of theaqueous antacid suspension.
 3. The suspension of claim 1 wherein said pHis about 8.0 to about 8.3.
 4. The suspension of claim 1 wherein saidthickening agent in step (b) is xanthan gum.
 5. The suspension of claim1 wherein said thickening agent is step (b) is xanthan gum premixed withglycerin.
 6. The suspension of claim 1 wherein said pH adjusting agentin step (c) is tartaric acid.
 7. The suspension of claim 1 furthercomprising (d) adding with stirring at least one pharmaceuticallyacceptable adjuvant or at any of steps (a), (b) or (c).
 8. Thesuspension of claim 7 wherein said adjuvant in step (d) is an effectiveantiflatulent amount of simethicone.
 9. The suspension of claim 7wherein said adjuvant in step (d) is an effective antiflatuent amount ofsimethicone, one or more preservatives, sorbitol and one or moreflavorants.
 10. The suspension of claim 1 wherein the amount of saidthickening agent is from about 0.1 to about 1.0 percent weight/volume,based on the volume of the aqueous antacid suspension.
 11. Thesuspension of claim 1 wherein said particle size distribution is about0.1 to about 10 microns.
 12. A stable aqueous antacid suspension fororal use with pH of about 8.0 to about 8.3 of calcium carbonate andmagnesium carbonate as the sole active antacid component, prepared by aprocess which comprises in the order specified the steps of:(a) addingto water an effective antacid amount of particulate calcium carbonateand particulate magnesium carbonate, each in the form of a micronizedpowder with 100% particle size distribution of about 0.1 to about 20microns with mixing until the particulate material is completely wettedand dispersed; (b) adding to said dispersion an effective suspendingamount of xanthan gum or xanthan gum premixed with glycerin, withstirring for a time sufficient to substantially coat said particulatematerial and to provide a suspension; and (c) adding to said suspensionwith stirring an effective pH adjusting amount of tartaric acid toprovide a pH of about 8.0 to about 8.3 to the final antacid suspension.13. The suspension of claim 12 further comprising (d) adding withstirring at least one pharmaceutically acceptable adjuvant or at any ofsteps (a), (b) or (c).
 14. The suspension of claim 12 wherein saidparticle size distribution is about 0.1 to about 10 microns.